Project Summary/Abstract Immunotherapy using monoclonal antibodies (mAbs) has proven successful in treating numerous diseases and is currently under investigation for the most common cause of dementia, Alzheimer's disease (AD). Extracellular plaques, containing amyloid beta (A?), and intraneuronal neurofibrillary tangles, composed of hyperphosphorylated tau, characterize AD pathology. A? accumulation begins prior to significant tau pathology, cerebral atrophy and the onset of dementia, yet amyloid-lowering treatments, including anti-A? antibodies, have not resulted in cognitive benefits for patients with mild to moderate dementia due to AD. While these treatments are re-evaluated in the earlier ?pre-clinical? stage of AD, before extensive A? pathology and cognitive symptoms, tau is emerging as another promising therapeutic target. The presence of tau deposits in specific brain regions correlates with cognitive decline in AD and in other neurodegenerative diseases, termed tauopathies, where tau inclusions alone are sufficient to cause degeneration. The Holtzman lab and others have shown that passive immunization with anti-tau mAbs reduces tau-associated pathology in murine models of tauopathy. Therefore, the overall objective of this proposal is to investigate ideal approaches to tau immunotherapy. A major limitation of passive immunization is the chronic high doses of mAbs required to reach therapeutic levels in the brain as only a small fraction cross the blood brain barrier. This proposal uses recombinant adeno-associated virus to express a chimeric full-length anti-tau mAb in the brain of a tauopathy mouse model. We hypothesize direct delivery of anti-tau mAbs to the brain by gene transfer will stimulate long- term expression in host cells that will reduce tau-associated pathology. Additionally, we have engineered anti- tau fragment antigen binding (Fab) domains and full-length chimeric mAbs in which the constant region of the heavy chain is replaced with immunoglobulin G (IgG) fragment crystallible (Fc) variants that exhibit differential binding to Fc? receptors. The IgG Fc domain binds to Fc? receptors primarily expressed on microglia in the brain and may mediate extracellular tau clearance, but can also lead to pro-inflammatory responses that may exacerbate the degenerative process. We will test the hypothesis that eliminating the IgG domain and Fc effector function of anti-tau mAbs avoids adverse pro-inflammatory effects while still providing neuroprotection by sequestering extracellular tau through direct administration of anti-tau Fab or full-length IgG Fc variants into the brain of a tauopathy mouse model. Thus, this proposal uses molecular approaches to investigate mechanisms of anti-tau immunotherapy and improve the efficiency of mAb delivery to the brain in order to advance passive immunization for brain derived antigens, like tau, and potentially lead to treatment options for the millions of people suffering from AD and related tauopathies.